Subtitles and Transcript

Svante Pääbo

0:11
What I want to talk to you aboutis what we can learn from studying the genomesof living peopleand extinct humans.But before doing that,I just briefly want to remind you about what you already know:that our genomes, our genetic material,are stored in almost all cells in our bodies in chromosomesin the form of DNA,which is this famous double-helical molecule.And the genetic informationis contained in the form of a sequenceof four basesabbreviated with the letters A, T, C and G.And the information is there twice --one on each strand --which is important,because when new cells are formed, these strands come apart,new strands are synthesized with the old ones as templatesin an almost perfect process.

0:58
But nothing, of course, in natureis totally perfect,so sometimes an error is madeand a wrong letter is built in.And we can then see the resultof such mutationswhen we compare DNA sequencesamong us here in the room, for example.If we compare my genome to the genome of you,approximately every 1,200, 1,300 letterswill differ between us.And these mutations accumulateapproximately as a function of time.So if we add in a chimpanzee here, we will see more differences.Approximately one letter in a hundredwill differ from a chimpanzee.

1:38
And if you're then interested in the historyof a piece of DNA, or the whole genome,you can reconstruct the history of the DNAwith those differences you observe.And generally we depict our ideas about this historyin the form of trees like this.In this case, it's very simple.The two human DNA sequencesgo back to a common ancestor quite recently.Farther back is there one shared with chimpanzees.And because these mutationshappen approximately as a function of time,you can transform these differencesto estimates of time,where the two humans, typically,will share a common ancestor about half a million years ago,and with the chimpanzees,it will be in the order of five million years ago.

2:24
So what has now happened in the last few yearsis that there are account technologies aroundthat allow you to see many, many pieces of DNA very quickly.So we can now, in a matter of hours,determine a whole human genome.Each of us, of course, contains two human genomes --one from our mothers and one from our fathers.And they are around three billion such letters long.And we will find that the two genomes in me,or one genome of mine we want to use,will have about three million differencesin the order of that.And what you can then also begin to dois to say, "How are these genetic differencesdistributed across the world?"And if you do that,you find a certain amount of genetic variation in Africa.And if you look outside Africa,you actually find less genetic variation.This is surprising, of course,because in the order of six to eight times fewer peoplelive in Africa than outside Africa.Yet the people inside Africahave more genetic variation.

3:28
Moreover, almost all these genetic variantswe see outside Africahave closely related DNA sequencesthat you find inside Africa.But if you look in Africa,there is a component of the genetic variationthat has no close relatives outside.So a model to explain thisis that a part of the African variation, but not all of it,[has] gone out and colonized the rest of the world.And together with the methods to date these genetic differences,this has led to the insightthat modern humans --humans that are essentially indistinguishable from you and me --evolved in Africa, quite recently,between 100 and 200,000 years ago.And later, between 100 and 50,000 years ago or so,went out of Africato colonize the rest of the world.

4:20
So what I often like to sayis that, from a genomic perspective,we are all Africans.We either live inside Africa today,or in quite recent exile.Another consequenceof this recent origin of modern humansis that genetic variantsare generally distributed widely in the world,in many places,and they tend to vary as gradients,from a bird's-eye perspective at least.And since there are many genetic variants,and they have different such gradients,this means that if we determine a DNA sequence --a genome from one individual --we can quite accurately estimatewhere that person comes from,provided that its parents or grandparentshaven't moved around too much.

5:09
But does this then mean,as many people tend to think,that there are huge genetic differences between groups of people --on different continents, for example?Well we can begin to ask those questions also.There is, for example, a project that's underwayto sequence a thousand individuals --their genomes -- from different parts of the world.They've sequenced 185 Africansfrom two populations in Africa.[They've] sequenced approximately equally [as] many peoplein Europe and in China.And we can begin to say how much variance do we find,how many letters that varyin at least one of those individual sequences.And it's a lot: 38 million variable positions.

5:54
But we can then ask: Are there any absolute differencesbetween Africans and non-Africans?Perhaps the biggest differencemost of us would imagine existed.And with absolute difference --and I mean a differencewhere people inside Africa at a certain position,where all individuals -- 100 percent -- have one letter,and everybody outside Africa has another letter.And the answer to that, among those millions of differences,is that there is not a single such position.This may be surprising.Maybe a single individual is misclassified or so.So we can relax the criterion a bitand say: How many positions do we findwhere 95 percent of people in Africa haveone variant,95 percent another variant,and the number of that is 12.

6:42
So this is very surprising.It means that when we look at peopleand see a person from Africaand a person from Europe or Asia,we cannot, for a single position in the genome with 100 percent accuracy,predict what the person would carry.And only for 12 positionscan we hope to be 95 percent right.This may be surprising,because we can, of course, look at these peopleand quite easily say where they or their ancestors came from.So what this means nowis that those traits we then look atand so readily see --facial features, skin color, hair structure --are not determined by single genes with big effects,but are determined by many different genetic variantsthat seem to vary in frequencybetween different parts of the world.

7:32
There is another thing with those traitsthat we so easily observe in each otherthat I think is worthwhile to consider,and that is that, in a very literal sense,they're really on the surface of our bodies.They are what we just said --facial features, hair structure, skin color.There are also a number of featuresthat vary between continents like thatthat have to do with how we metabolize food that we ingest,or that have to dowith how our immune systems deal with microbesthat try to invade our bodies.But so those are all parts of our bodieswhere we very directly interact with our environment,in a direct confrontation, if you like.It's easy to imaginehow particularly those parts of our bodieswere quickly influenced by selection from the environmentand shifted frequencies of genesthat are involved in them.But if we look on other parts of our bodieswhere we don't directly interact with the environment --our kidneys, our livers, our hearts --there is no way to say,by just looking at these organs,where in the world they would come from.

8:42
So there's another interesting thingthat comes from this realizationthat humans have a recent common origin in Africa,and that is that when those humans emergedaround 100,000 years ago or so,they were not alone on the planet.There were other forms of humans around,most famously perhaps, Neanderthals --these robust forms of humans,compared to the left herewith a modern human skeleton on the right --that existed in Western Asia and Europesince several hundreds of thousands of years.So an interesting question is,what happened when we met?What happened to the Neanderthals?

9:23
And to begin to answer such questions,my research group -- since over 25 years now --works on methods to extract DNAfrom remains of Neanderthalsand extinct animalsthat are tens of thousands of years old.So this involves a lot of technical issuesin how you extract the DNA,how you convert it to a form you can sequence.You have to work very carefullyto avoid contamination of experimentswith DNA from yourself.And this then, in conjunction with these methodsthat allow very many DNA molecules to be sequenced very rapidly,allowed us last yearto present the first version of the Neanderthal genome,so that any one of youcan now look on the Internet, on the Neanderthal genome,or at least on the 55 percent of itthat we've been able to reconstruct so far.And you can begin to compare it to the genomesof people who live today.

10:21
And one questionthat you may then want to askis, what happened when we met?Did we mix or not?And the way to ask that questionis to look at the Neanderthal that comes from Southern Europeand compare it to genomesof people who live today.So we then lookto do this with pairs of individuals,starting with two Africans,looking at the two African genomes,finding places where they differ from each other,and in each case ask: What is a Neanderthal like?Does it match one African or the other African?We would expect there to be no difference,because Neanderthals were never in Africa.They should be equal, have no reason to be closerto one African than another African.And that's indeed the case.Statistically speaking, there is no differencein how often the Neanderthal matches one African or the other.But this is differentif we now look at the European individual and an African.Then, significantly more often,does a Neanderthal match the Europeanrather than the African.The same is true if we look at a Chinese individualversus an African,the Neanderthal will match the Chinese individual more often.This may also be surprisingbecause the Neanderthals were never in China.

11:40
So the model we've proposed to explain thisis that when modern humans came out of Africasometime after 100,000 years ago,they met Neanderthals.Presumably, they did so first in the Middle East,where there were Neanderthals living.If they then mixed with each other there,then those modern humansthat became the ancestorsof everyone outside Africacarried with them this Neanderthal component in their genometo the rest of the world.So that today, the people living outside Africahave about two and a half percent of their DNAfrom Neanderthals.

12:17
So having now a Neanderthal genomeon hand as a reference pointand having the technologiesto look at ancient remainsand extract the DNA,we can begin to apply them elsewhere in the world.And the first place we've done that is in Southern Siberiain the Altai Mountainsat a place called Denisova,a cave site in this mountain here,where archeologists in 2008found a tiny little piece of bone --this is a copy of it --that they realized came from the last phalanxof a little finger of a pinky of a human.And it was well enough preservedso we could determine the DNA from this individual,even to a greater extentthan for the Neanderthals actually,and start relating it to the Neanderthal genomeand to people today.And we found that this individualshared a common origin for his DNA sequenceswith Neanderthals around 640,000 years ago.And further back, 800,000 years agois there a common originwith present day humans.

13:25
So this individual comes from a populationthat shares an origin with Neanderthals,but far back and then have a long independent history.We call this group of humans,that we then described for the first timefrom this tiny, tiny little piece of bone,the Denisovans,after this place where they were first described.So we can then ask for Denisovansthe same things as for the Neanderthals:Did they mix with ancestors of present day people?If we ask that question,and compare the Denisovan genometo people around the world,we surprisingly findno evidence of Denisovan DNAin any people living even close to Siberia today.But we do find it in Papua New Guineaand in other islands in Melanesia and the Pacific.So this presumably meansthat these Denisovans had been more widespread in the past,since we don't think that the ancestors of Melanesianswere ever in Siberia.

14:24
So from studyingthese genomes of extinct humans,we're beginning to arrive at a picture of what the world looked likewhen modern humans started coming out of Africa.In the West, there were Neanderthals;in the East, there were Denisovans --maybe other forms of humans toothat we've not yet described.We don't know quite where the borders between these people were,but we know that in Southern Siberia,there were both Neanderthals and Denisovansat least at some time in the past.Then modern humans emerged somewhere in Africa,came out of Africa, presumably in the Middle East.They meet Neanderthals, mix with them,continue to spread over the world,and somewhere in Southeast Asia,they meet Denisovans and mix with themand continue on out into the Pacific.And then these earlier forms of humans disappear,but they live on a little bit todayin some of us --in that people outside of Africa have two and a half percent of their DNAfrom Neanderthals,and people in Melanesiaactually have an additional five percent approximatelyfrom the Denisovans.

15:35
Does this then mean that there is after allsome absolute differencebetween people outside Africa and inside Africain that people outside Africahave this old component in their genomefrom these extinct forms of humans,whereas Africans do not?Well I don't think that is the case.Presumably, modern humansemerged somewhere in Africa.They spread across Africa also, of course,and there were older, earlier forms of humans there.And since we mixed elsewhere,I'm pretty sure that one day,when we will perhaps have a genomeof also these earlier forms in Africa,we will find that they have also mixedwith early modern humans in Africa.

16:17
So to sum up,what have we learned from studying genomesof present day humansand extinct humans?We learn perhaps many things,but one thing that I find sort of important to mentionis that I think the lesson is that we have always mixed.We mixed with these earlier forms of humans,wherever we met them,and we mixed with each other ever since.